Haldane's Dilemma

Introduction

In recent years, creationist Walter ReMine has been making claims that
the evolution from the common ancestor of humans and other apes to humans
could not have happened in five million years because of a concept known
as "Haldane's Dilemma". Haldane's Dilemma is based upon the substitution
cost introduced by J.B.S. Haldane in his classic 1957 paper "The
Cost of Natural Selection"(Haldane, 1957). ReMine addresses
these issues in his book "The Biotic Message" (ReMine, 1993). ReMine also
claims that the scientific community has "brushed aside" and never properly
responded to Haldane's Dilemma. The purpose of this essay is to show that
ReMine's arguments are false (or at least greatly exaggerated), and were
answered decades before "The Biotic Message" was even published.

Haldane calculated the substitution cost based upon a scenario where
a sudden environmental change makes genes that were formerly detrimental
and very rare become favorable. The genes begin the process of becoming
common (because they are now favored by natural selection) and eventually
are fixed in the population - present in virtually every individual). Under
Haldane's deteriorating environment scenario, huge numbers of deaths will
occur in the population because for most of the substitution, only a few
individuals will have the beneficial genes that protect them from the environmental
change.

William Feller, P.A.P. Moran, and Joe Felsenstein all proposed that
Haldane's Dilemma did not apply to beneficial mutations (mutations that
produce genes that benefit the organism without a change to the
environment that is detrimental to all of the organisms not carrying the
mutated gene). This makes perfect sense because you will not see the huge
numbers of deaths (an average 30 times the population size in the case
of diploids, according to Haldane) required to make the replacement of
a beneficial mutation that you will see in the case Haldane describes,
where there has been a deterioration in the environment. However, Motoo
Kimura (who used Haldane's Dilemma as a justification for his Neutral
Theory) had a response to this claim. He pointed out that in order for
beneficial mutations to explain the genetic differences seen in mammals,
huge (ridiculous, like 1078 offspring per individual each generation)
numbers of offspring would be required. Kimura used these arguments as
part of the evidence to support his neutral theory of evolution - the idea
that most (but not all) gene substitutions seen in evolution have little
or no effect upon the fitness of species. In response to Kimura, Warren
Ewens demonstrated that the ridiculous numbers of offspring are not required
to drive the simultaneous selection of many beneficial mutations in a finite
population.

What is Haldane's
Dilemma?

Haldane claimed that in a fixed population (a population that is neither
growing nor shrinking in the number of its member animals) of relatively
slowly reproducing mammals, no more than 1 gene could be fixed per 300
generations due to the cost of substitution. Haldane assumed that the deaths
caused by the newly disadvantageous gene's lower fitness (possibly due
to a change in environment) would be over and above the "background" death
rate - the naturally occurring deaths due to all reasons other than the
lowered fitness of the gene. Haldane estimated that the substitution cost
(for a diploid) would require the deaths of 30 times the population size
for a single gene fixation from a very rare mutation to homozygous for
the entire population. Since he claimed that the intensity of selection
rarely exceeded 10%, Haldane believed a cost of 30 times the population
size for the substitution would require 300 generations (30 / 0.1) to fix
a single gene.

Haldane seemed satisfied that this rate of substitution was sufficient
to explain theorized substitution rates at the time (see
pg. 521 of "The Cost..."), but other scientists felt this rate
was too low. The first mention of the term "Haldane's Dilemma" appears
to come from paleontologist Leigh Van Valen in his 1963 paper "Haldane's
Dilemma, Evolutionary Rates, and Heterosis" (Van Valen, 1963). Van Valen
saw the dilemma as the observation that "for most organisms, rapid turnover
in a few genes precludes rapid turnover in the others." Haldane's dilemma
has come to mean this limit upon the rate of evolution.

What
is the Substitution Cost?

Very simply, the substitution cost (or cost of natural selection) as
defined by Haldane is the number of deaths (normalized to the population
size) required for a substitution to occur. Thus, when Haldane states that
a substitution cost of 30 is typical for a substitution for a diploid organism,
he is saying that such a substitution would require the deaths of 30 times
the population size. Therefore, if the population size was 100,000, 30
* 100,000 or 3 million deaths would be required for the substitution to
occur. I have assembled a series of quotes
from Haldane from "The Cost of Natural Selection" to document this
definition. The fact that the substitution cost represents the number of
deaths required for the substitution to occur should also be apparent from
the derivations for the cost that are linked below.

ReMine claims that Haldane's Dilemma shows that not "enough" genes could
have substituted in the human species since the last common ancestor with
other apes. I shall illustrate each of these by quotes from ReMine "The
Biotic Message" and from the thread "Haldane's Cost of Natural Selection"
in sci.bio.evolution.

From page 209 of "The Biotic Message":
With these clarifications, let us return to the example.
Take an ape-like creature from 10 million years ago, substitute a maximum
of 500,000 selectively significant nucleotides and would you have a poet
philosopher? How much information can be packed into 500,000 nucleotides?
It is roughly one-hundredth of one percent of the nucleotide sites in each
human ovum.

Is this enough to account for the significantly improved
skull, jaws,teeth, feet, upright posture, abstract thought, and appreciation
of music, to name just a few? If you find it doubtful, then you are beginning
to understand why this is important. It sets a limit on the number of traits
that can be substituted by differential survival in the available time.

This quote is taken from ReMine's post to the usenet discussion group
sci.bio.evolution on 01/28/1998, Message-ID: <6anste$qd6$1@nntp6.u.washington.edu>.
Here he lays out his claim that Haldane's Dilemma allows only 1,667 substitutions
to occur in the last ten million years of evolution leading to the human
lineage. ReMine's quote follows:

As an example my book focuses on human evolution from
its presumed ancestor (whatever it might be) from, say, ten million years
ago. That is twice as old as the alleged split between gorilla, chimpanzee,
and man. My book cites evolutionists such as Dawkins, Stebbins, Kimura
and Ohta for an estimate of the effective generation time during that era
-- twenty years. That makes for 500,000 generations. Then apply the Haldane
limit of one substitution per 300 generations, and apply the evolutionary
model exactly as taught in the textbooks. The result: In ten million years
the population could substitute no more than 1,667 beneficial nucleotides.
That is not remotely enough to explain human evolution.

ReMine also implies that Haldane's Dilemma is a problem for the genetic
differences seen between humans and chimpanzees in this statement attributed
to ReMine on a page maintained by creationist Ted
Holden:

Imagine a population of 100,000 of those organisms quietly
evolving their way to humanity. For easy visualization, I'll have
you imagine a scenario that favors rapid evolution. Imagine evolution
happens like this. Every generation, one male and one female receive
a beneficial mutation so advantageous that the 999,998 others die off immediately,
and the population is then replenished in one generation by the surviving
couple. Imagine evolution happens like this, generation after generation,
for ten million years. How many beneficial mutations could be substituted
at this crashing pace? One per generation -- or 500,000 nucleotides.
That's 0.014 percent of the genome. (That is a minuscule fraction of the
2 to 3 percent that separates us from chimpanzees).

I have read "The Biotic Message", and I am aware that ReMine does not stress
the issue of the "2 to 3 percent" difference that separates humans and
chimps in that book. However, unless Holden has incorrectly attributed
the passage above to ReMine, ReMine does try to make an issue of those
differences. Furthermore, this form of the argument is often seen
on the Internet and also was printed in the creationist publication Creation
Ex Nihlio 19(1):21-22, Dec. 1996-Feb. 1997.- see Does
the DNA similarity between chimps and humans prove a common ancestry?.
In item 6 of the essay, Batten refers to the 120 million differences between
humans and chimps (because he used a difference of 4%). In footnote 7 of
the article, Batten specifically refers to "The Biotic Message" and its
treatment of Haldane's Dilemma as evidence that the number of differences
seen between humans and chimps is impossible to explain. So even though
ReMine does not stress this issue in "The Biotic Message", because creationists
are in fact using the argument that a "2 to 3 percent" genetic difference
between chimps and humans is a problem for evolution because of Haldane's
Dilemma, it is very important that these arguments are addressed. One important
thing ignored by these claims of ReMine and other creationists is the simple
fact that neutral substitutions do not add to Haldane's substitution
cost and are not part of Haldane's Dilemma.

Solutions
to Haldane's Dilemma

There may not be a DilemmaThere is basically a very simple solution to Haldane's Dilemma as presented
by ReMine: 1 (beneficial) gene substitution per 300 generations could be
enough to account for human evolution. Although 1,667 substitutions may
seem like a low number, it may be sufficient to explain the differences
between humans and their ancestors of 10 million years ago. There is no
way to determine the genetic differences between humans and those ancestors
(because the ancestors are not available for genetic testing). No scientist
currently knows the number of non neutral substitutions that have occurred
during this time period. (Nor does ReMine, despite his exaggerated claims
to the otherwise.) In fact, evidence is beginning to accumulate that the
genetic differences between related species is due to rather few genetic
differences of large effect - see The
Genetic Basis of Evolution to learn more about this fascinating development.
It is hard to get concerned about a dilemma when it hasn't even been shown
to exist. The pertinent question to ask of ReMine and his followers is:
What is the hard evidence that more than 1,667 beneficial substitutions
are required between humans and chimps? Remember, only the substitution
of beneficial (fitness enhancing) alleles will add to the substitution
cost as defined by Haldane. Fixation of neutral alleles (the vast majority
of substitutions that have occurred in the human and chimp lines since
they last shared a common ancestor) does not add to the substitution cost.

In fact, to the best of my knowledge, only one genetic difference has
been determined to date that produces a significant difference between
humans and apes. This is a change in the structure of sialic acid, which
is different in humans from all other mammals. These sialic acids are components
of cell membranes throughout the body and are involved in brain development,
messaging between cells, and are targets of disease organisms when they
infect cells. You can read the original scientific paper on this "A
mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan
divergence" online. Also, see the popular articles Which
of Our Genes Make Us Human? by Ann Gibbons and Pinpointing
how humans differ from apes. These changes were traced back to a single
genetic change (a 92 base pair deletion in the gene that codes the hydroxylase
enzyme that adds an oxygen atom to sialic acid). Additionally, here is
a follow up paper from some members of the team that discovered the sialic
acid difference between humans and apes: Genetic
Differences between Humans and Great Apes. The authors have suggestions
on how to proceed with determining the significant genetic differences
between humans and chimps.

Just because the number of gene substitutions that have occurred in
the recent human lineage is unknown doesn't mean that the issue is being
ignored. The first part of answering this question is well under way. The
Human
Genome Project is an ongoing 15 year long mission of the scientific
community to identify all human genes (approximately 35,000 of them) and
sequence all 3 billion DNA base pairs. The second part to determining whether
or not Haldane's Dilemma even exists will be to map the genome of our closest
living relatives, the chimpanzee, the gorilla, and the orang-utan. The
Chimpanzee Genome Project is being proposed (A
Chimpanzee Genome Project Is a Biomedical Imperative and here)
to take advantage of the new DNA chip technology and knowledge gained from
the Human Genome Project to map the chimpanzee genome far more quickly
and more economically than was the case for the Human Genome Project.
Once this has been done, differences between the human and chimpanzee can
be identified and evaluated. A count of the non neutral substitutions that
have occurred in the two lineages can then be made (although it may not
be easy to determine which substitutions have a major effect upon fitness).
Only at that point will we know whether or not Haldane's Dilemma is even
an issue of concern for human evolution. Considering these facts, it is
clear to see that ReMine and his followers are greatly exaggerating this
issue.

Additionally, Project
Silver is underway to sequence the ape genomes and compare them nucleotide
by nucleotide to the human genome in an effort to determine "which of our
genes make us human." Notice that on this Project
Silver introduction page, we see speculation that the significant changes
between humans and chimps may be in the neighborhood of 10,000. Although
the author of the page clearly states that this is a "very rough guess",
it is worth noting that this is far less than ReMine's uninformed claims
that 500,000 such changes are insufficient to explain the last 10 million
years of human evolution. It is also significant that the estimate of 10,000
important differences was made before the rough draft of the human genome
project became available in Feb. of 2001, when it was learned that only
1.1% of the human genetic material encodes genes. The Project Silver page
appears to use 5% as the estimate of gene encoding DNA, so if they scale
back the number of "significant" genes that differ between humans
and chimps by this factor of 5, they are very close to the range permitted
by Haldane (2,000 significant changes vs. 1,667 "permitted" by Haldane
). An important observation to make here is that while creationists like
ReMine and his followers falsely charge that "Haldane's Dilemma" makes
evolution impossible and evolutionists are covering up or ignoring the
facts, the scientists are in reality doing everything they can to detect
the genetic differences between humans and chimps and get those results
published.

The Cost of Beneficial
Substitutions and Soft SelectionRemember that Haldane defined the substitution cost as the number of
deaths required for the substitution. He estimated that for a diploid species,
that number would typically be 30 times the population size. The immediately
obvious question is why is this number so high? If a trait is present in
a few individuals, if all remaining members of the population (that don't
have the trait) were wiped out, the substitution would occur with the death
of only 1 times the population size individuals - not 30 times the population
size. Admittedly, this is a little weak in that the population would still
require time to build up to its former numbers, but it begins to point
out the fact that the deaths of large multiples of the population size
individuals is not required to drive a substitution. In fact, it has been
shown that in two situations (besides the unrealistic one I have just mentioned),
a single substitution can occur with the death of only 1 times the population
size rather than a factor of (typically) 30.

To see why and how this is possible, we have to look at Haldane's assumptions
of how substitutions occurred in his derivations of the substitution cost.

Haldane considered the effects of a change in the environment. From
page 514 of "The Cost of Natural Selection":

I shall investigate the following case mathematically. A
population is in equilibrium under selection and mutation. One or more
genes are rare because their appearance by mutation is balanced by natural
selection. A sudden change occurs in the environment, for example, pollution
by smoke, a change of climate, the introduction of a new food source, predator,
or pathogen, and above all migration to a new habitat. It will be shown
later that the general conclusions are not affected if the change is slow.
The species is less adapted to the new environment, and its reproductive
capacity is lowered. It is gradually improved as a result of natural
selection. But meanwhile, a number of deaths, or their equivalents in lowered
fertility, have occurred. If selection at the ith selected locus
is responsible for di of these deaths in any generation the
reproductive capacity of the species will be P(1
- di) of that of the optimal genotype, or exp(-Sdi
) nearly, if every di is small. Thus the intensity of selection
approximates toSdi.

The interesting thing (as pointed out by Leigh Van Valen and Bruce Wallace)
is to look at what happens under different conditions than those envisioned
by Haldane. If one looks at the substitution of a new, beneficial allele,
it is apparent that the number of genetic deaths required for the substitution
is 1 (times the population size), not the large factors of the population
size that Haldane calculated under the deteriorating environment scenario.
The reason for this is that there is no longer the relentless culling of
the vast majority of the population as is the case for the deteriorating
environment. Although individuals carrying the beneficial allele will eventually
eliminate the remaining population, the effects of this replacement will
not be felt until the new allele has become fairly common. Some scientists
(George Williams) have claimed that soft selection is not common in nature,
but, beneficial mutations will always behave like soft selection.
This is because whenever a beneficial allele is created (through a mutation),
although the individuals carrying the new allele will have a higher fitness,
the remaining members of the population will not have a large decrease
in fitness. This is part of the reason that Feller and Moran rejected Haldane's
high cost arguments for beneficial substitutions. See Substitution
of a Beneficial Allele, Diploid for the mathematical details of how
the substitution cost is lowered in the case of beneficial alleles.

Multiple Simultaneous
Substitutions Lower the Cost Even FurtherIt is easy to see that the substitution cost is lowered when multiple
substitutions are occurring in a population. The reason for this is very
simple. If two beneficial mutations are moving towards fixation in a population,
whenever an organism that carries neither of those mutations dies, the
cost of substitution is exactly half what it would have been had the two
substitutions occurred at different times from one another. One organism
has died to "pay the cost" for two substitutions. If you prefer to look
at the cost from the perspective of the number of individuals that must
be born to carry the mutation to fixation, then one individual which is
born with two beneficial genes (and survives to reproduce) pays the cost
that would have been required of two organisms if the substitutions had
occurred separately. As more substitutions are going on at the same time,
the more the cost will be lowered (compared to what the cost would have
been had the substitutions occurred separately. Evidence that this actually
occurs in nature has recently been discovered. Scientists have recently
determined that the genes
driving the speciation of a particular group of aphids lie very close to
one another on the same chromosome. When genes are closer together
on a chromosome (tightly linked), they are more likely to move together
as a single unit because they are not broken up by recombination.
This will lower the substitution cost even more than the simultaneous substitution
of unlinked genes.

Haldane did address the issue of multiple simultaneous substitutions
in "The Cost of Natural Selection" (see the fifth paragraph of page 511).
However, because he considered only substitutions occurring in the deteriorating
environment scenario, he did not think that very many substitutions could
occur simultaneously. He gave the example of a change in the environment
that suddenly favored 10 rare alleles, leaving the fitness of any individual
carrying all 10 of those alleles unchanged and reducing the fitness of
all individuals not carrying all 10. If each of the 10 alleles is rare,
the vast majority of the population would carry none of the 10. If the
fitness of an organism is reduced by 1/2 for each of the 10 beneficial
alleles it does not have, then the fitness of the vast majority of the
population would be reduced by a factor of 1024. Haldane pointed out that
such a fitness reduction could not be tolerated by the vast majority of
species in the world. However, when substitutions occur that are truly
beneficial (when the environment is not deteriorating), then the
fact that the vast majority of the population does not possess any of the
beneficial mutations does not lead to any reduction in fitness. Individuals
without the beneficial mutations have the same fitness that they did before.
Individuals that do not have the beneficial mutations will only see a decrease
in fitness when the individuals carrying the beneficial mutations become
more common in the population and begin to out compete those without the
beneficial mutations for resources.

Kimura on the Substitution
Cost as Evidence for the Neutral Theory - A Fly in the Ointment?After demonstrating that that any beneficial substitution or any substitution
under the soft selection scenario would not require the death of typically
30 times the population size for a diploid organism, it is not surprising
that many scientists (i.e. Van Valen, Feller, Wallace) thought Haldane's
Dilemma was solved. However, Motoo Kimura, who used Haldane's arguments
as evidence to support his neutral theory, had an answer for those who
thought beneficial mutations or soft selection could be used to escape
Haldane's Dilemma. Kimura made estimates of the substitution rate of about
1 amino acid per every 2 years (Kimura 1968), and later 6 amino acid substitutions
per generation (Ewens 1979, pg. 252). Kimura based these rates upon comparisons
of amino acid substitutions that had occurred among various species in
the genes that code for hemoglobin, cytochrome c, and triosephosphate dehydrogenase.
Note that when researchers looked at substitution rates for a wider variety
of proteins and organisms, they found an amino acid substitution rate of
1 substitution per 36 years (about 1 substitution per 18 generations for
most mammals), far slower than that calculated by Kimura (recounted in
Spiess 1977). At any rate, based upon the rates calculated by Kimura, in
order for a population to drive substitutions at the rates suggested by
protein comparisons among different species, huge numbers of offspring
would have to be produced by each parent. A quote from Kimura and Ohta
(Ewens 1979) addresses the offspring requirements required to drive six
substitution per year:

"to carry out mutant substitution at the above rate, each
parent must leave e180
1078 offspring for only one of the offspring to survive. This
was the main reason why random fixation of selectively neutral mutants
was first proposed by one of us as the main factor in molecular evolution."

Kimura thought the huge offspring requirement generated by the substitution
cost (if all substitutions were driven by natural selection) was strong
evidence for his neutral theory (that a large number of amino acid substitutions
was driven by random drift of selectively neutral gene variants rather
than by natural selection of alleles having varying fitnesses). Kimura
never thought that Haldane's Dilemma was a "problem" for evolution, only
that it was good evidence that the bulk of observed substitutions between
related species were neutral rather than selected. Some have argued that
these huge offspring requirements are not the same as the substitution
cost as defined by Haldane. Since the offspring requirement to drive a
substitution is not exactly the same as the number of selective deaths
required to drive the substitution (Haldane's definition
of the substitution cost), these arguments may have some merit. Nonetheless,
since it has already been shown that the substitution of beneficial alleles
in a non-deteriorating environment will not lead to the huge costs
(numbers of selective deaths) predicted by Haldane, the huge numbers of
reproductive excess required by Kimura's arguments are the only way to
carry Haldane's cost arguments forward into the non-deteriorating environment.
If it were not for this tremendous offspring requirement, Haldane's Dilemma
would have been entirely solved by the soft selection / beneficial trait
arguments of Van Valen, Feller, and Walace. Regardless of where you stand
on this issue, as will be shown in the next section, Warren Ewens was able
to show substitutions could easily be driven at the observed rates in finite
populations without the huge offspring requirements calculated by Kimura.

As an aside, if the rate of 1 substitution per 36 years (as mentioned
above) is correct, this would indicate that in 10 million years, we would
expect about 280,000 substitutions to occur. This rate (based upon observed
amino acid differences in organisms) is slightly over half the number
of substitutions (500,000) that ReMine thinks is insufficient to explain
the last 10 million years of human evolution. Clearly, ReMine has no clue
as to the number of selectively significant substitutions required to explain
human evolution.

The Cost is So Much Lower
in Finite Populations that it is Not an Issue - Ewens Answers Kimura's
ObjectionsIn two papers (Ewens 1970, Ewens 1972), Warren Ewens showed that the
substitution cost was greatly reduced when realistic population sizes are
considered. In fact, he showed that a finite population was capable of
bearing the substitution cost required for even the highest substitution
rates inferred from the sequencing of proteins across various species.

Ewens showed that a significant amount of the cost of natural selection
was due to differences between the fittest members of a population and
the mean. To get at the mathematics of multiple substitutions, Ewens described
a scenario where alleles begin moving towards fixation at regular intervals.
For example, in a particular generation, one allele begins moving toward
fixation (because of natural selection), and 10 generations later a second
allele (at a different position than the first allele - on a different
gene) begins moving towards fixation, and 10 generations later a third
allele begins moving towards fixation, etc. To make it possible to do the
math, each of these alleles have the same parameters (selection coefficient,
coefficient of dominance, starting frequency, and ending frequency). If
it takes say 200 generations for each substitution to complete, then there
will be 20 substitutions going on at any one time (after the process has
been going on long enough for 20 to have started). Ewens showed that the
substitution load for a single generation (which he and Kimura identify
as being the same as the substitution cost and the cost of natural selection)
is given by the difference between the optimal genotype (the genotype that
has all 20 of the favored alleles) and the average genotype. The problem
that Ewens pointed out is that it is highly unlikely that any individuals
of the optimal genotype will even exist in a finite population. This is
due to the fact of the rarity of some of the favored alleles in the population
because they have only recently started moving towards fixation. Notice
that half of the favored alleles will have frequencies of 50% or less,
making it highly unlikely that even one individual will exist with all
or even a very large majority of the favored alleles in a finite population.

Ewens then used the statistics of extreme values to determine that it
was unlikely that any individual would exist with a fitness more than 4
standard deviations above the average fitness in a finite population (a
population of 100,000). He then showed that this fact greatly reduced the
substitution load for multiple substitutions in a finite population. Ewens
showed that a diploid animal species could drive up to 6 beneficial substitutions
per generation with a reproductive output of 1.98 children per parent (meaning
that each couple needs to have about 4 children - something even the most
slowly reproducing mammalian species are capable of). There is at least
one possible criticism of Ewens' demonstration that 2 offspring per parent
is sufficient to drive the number of substitutions actually observed in
genetic comparisons of various animals. This is the fact that the reproductive
excess of 0.98 offspring per parent to drive the substitution, while
well within the capabilities of even the most slowly reproducing species,
is nonetheless higher than the amount estimated by Haldane (0.1 or 10%).
There are several answers to this objection. The first is that Haldane
did not make a very good case for the 10% reproductive excess limit. Haldane
makes no case for this figure in "The Cost..." other than to note that
the selection intensity on babies born in London (in the late 1940's, I
believe - not exactly the most selective environment in the world, to say
the least) demonstrated a selection intensity of 3% based upon birth weight
(pg. 512). In fact, Haldane later mentions that the selection intensity
in the peppered moth (Biston betularia) around 0.5 (50%) on pg. 521. Therefor
it is not terribly surprising that some find Haldane's claim that the intensity
of natural selection rarely exceeds 10% to be questionable (and at least
worthy of further investigation). Another consideration that must be made
is that the reproductive excess requirement predicted by Ewens is dependent
upon the selection coefficient.

Future DirectionsThere is still much to be learned about the process of natural selection
and genome changes over time. Creationists like Walter ReMine seem to operate
under the mistaken impression that scientists are engaged in a gigantic
conspiracy to "obscure" and "brush aside" Haldane's Dilemma and other problems
with the theory of evolution. In order to know whether or not the the substitution
cost even has the potential to be an issue in real world evolution, there
is still much to learn. One thing that has to be determined is the number
of genetic differences between humans and chimps that were actually driven
by natural selection. The first step will be to identify the genetic differences
between humans and chimps. Then those differences will have to be evaluated
to determine which of those genetic differences have any effect upon human
or chimp fitness - these are the only ones that may have been driven by
natural selection. Only when we have some kind of idea of the number of
substitutions that actually affect fitness will we even know whether or
not "Haldane's Dilemma" is even an issue for human evolution. If the number
of substitutions is less than Haldane's limit (1,667 for the human / chimp
lines), then Haldane's Dilemma is not an issue at all. If the number is
greater than 1,667 fitness enhancing substitutions, then the nature of
natural selection as it actually occurs in the wild will need to be examined
carefully. Is the hard selection, deteriorating environment scenario as
envisioned by Haldane always (or mostly) the case, or is the environment
always deteriorating but selection is soft, or will the fixation of positive,
fitness enhancing mutations be common? Each of these scenarios play a role
in how high the substitution cost is, and we will never have any idea of
whether or not the cost is really a factor in human evolution without a
detailed understanding of how natural selection actually operates in nature.
Scientists are currently working on the answers to most (if not all) of
these questions.

Conclusion

Remember, Haldane's 1957 paper was a theoretical treatise on
the cost of natural selection. Here is Haldane's conclusion, which is correct
in both points:
"To conclude, I am quite aware that my conclusions
will probably need drastic revision. But I am convinced that quantitative
arguments of the kind here put forward should play a part in all future
discussions of evolution."